Aryl substituted pyridines and the use thereof

ABSTRACT

This invention relates aryl substituted pyridines of Formula I: 
                         
or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein Ar and R 1 -R 4  are set in the specification. The invention is also directed to the use of compounds of Formula I for the treatment of neuronal damage following global and focal ischemia, for the treatment or prevention of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), and for the treatment, prevention or amelioration of both acute or chronic pain, as antitinnitus agents, as anticonvulsants, and as antimanic depressants, as local anesthetics, as antiarrhythmics and for the treatment or prevention of diabetic neuropathy.

This application is a divisional of application Ser. No. 11/518,448,filed Sep. 11, 2006, now U.S. Pat. No. 7,579,367 B2, which is adivisional of application Ser. No. 10/235,673, filed Sep. 6, 2002, nowU.S. Pat. No. 7,105,549 B2, which claims the priority benefit under 35U.S.C. §119(e) of U.S. Provisional Application No. 60/317,526, filedSep. 7, 2001, the entirety of which is incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is in the field of medicinal chemistry. In particular,the invention relates to novel aryl substituted pyridines and thediscovery that these compounds act as blockers of sodium (Na⁺) channels.

2. Related Art

Several classes of therapeutically useful drugs, including localanesthetics such as lidocaine and bupivacaine, antiarrhythmics such aspropafenone and amioclarone, and anticonvulsants such as lamotrigine,phenytoin and carbamazepine, have been shown to share a common mechanismof action by blocking or modulating Na⁺ channel activity (Catterall, W.A., Trends Pharmacol. Sci. 8:57-65 (1987)). Each of these agents isbelieved to act by interfering with the rapid influx of Na⁺ ions.

Recently, other Na⁺ channel blockers such as BW619C89 and lifarizinehave been shown to be neuroprotective in animal models of global andfocal ischemia and are presently in clinical trials (Graham et al., J.Pharmacol. Exp. Ther. 269:854-859 (1994); Brown et al., British J.Pharmacol. 115:1425-1432 (1995)).

The neuroprotective activity of Na⁺ channel blockers is due to theireffectiveness in decreasing extracellular glutamate concentration duringischemia by inhibiting the release of this excitotoxic amino acidneurotransmitter. Studies have shown that unlike glutamate receptorantagonists, Na⁺ channel blockers prevent hypoxic damage to mammalianwhite matter (Stys et al., J. Neurosci. 12:430-439 (1992)). Thus, theymay offer advantages for treating certain types of strokes or neuronaltrauma where damage to white matter tracts is prominent.

Another example of clinical use of a Na⁺ channel blocker is riluzole.This drug has been shown to prolong survival in a subset of patientswith ALS (Bensimm et al., New Engl. J. Med. 330:585-591 (1994)) and hassubsequently been approved by the FDA for the treatment of ALS. Inaddition to the above-mentioned clinical uses, carbamazepine, lidocaineand phenytoin are occasionally used to treat neuropathic pain, such asfrom trigeminal neurologia, diabetic neuropathy and other forms of nervedamage (Taylor and Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)),and carbamazepine and lamotrigine have been used for the treatment ofmanic depression (Denicott et al., J. Clin. Psychiatry 55: 70-76(1994)). Furthermore, based on a number of similarities between chronicpain and tinnitus, (Moller, A. R. Am. J. Otol. 18: 577-585 (1997);Tonndorf, J. Hear. Res. 28: 271-275 (1987)) it has been proposed thattinnitus should be viewed as a form of chronic pain sensation (Simpson,J. J. and Davies, E. W. Tip. 20: 12-18 (1999)). Indeed, lignocaine andcarbamazepine have been shown to be efficacious in treating tinnitus(Majumdar, B. et al. Clin. Otolaryngol. 8: 175-180 (1983); Donaldson, I.Laryngol. Otol. 95: 947-951 (1981)).

It has been established that there are at least five to six sites on thevoltage-sensitive Na⁺ channels which bind neurotoxins specifically(Catterall, W. A., Science 242:50-61 (1988)). Studies have furtherrevealed that therapeutic antiarrhythmics, anticonvulsants and localanesthetics whose actions are mediated by Na⁺ channels, exert theiraction by interacting with the intracellular side of the Na⁺ channel andallosterically inhibiting interaction with neurotoxin receptor site 2(Catterall, W. A., Ann. Rev. Pharmacol. Toxicol. 10:15-43 (1980)).

JP 07076542 A2 describes liquid crystals and liquid crystal compositionscomprising the following compounds:

U.S. Pat. No. 5,403,934 describes the following intermediates forpreparing antimalarials:

Liao et al. (J. Heterocycl. Chem. 13:1283-1288 (1976)) describe thefollowing formula:

Salman (Pharmazie 54:178-183 (1999)) describes anantibacterial/antifungal compound of formula:

wherein Y is NHMe or OMe.

WO 9938829 describes a compound of formula:

This compound is described to be useful as an immunosuppressant or anantiallegy agent.

Karamysheva et al. (Mol. Cryst. Liq. Cryst. 67:241-251 (1981)) describecompounds of formula:

wherein Y is a straight chain C₄-C₈ alkyl or alkoxy.

DE 3245950 describes a compound of the following formula that isdescribed to be useful as an antihypertensive:

U.S. Pat. No. 4,920,119 describes several2-phenyl-3-aminopyridine-4-carboxamide derivatives as reactants.

Troschuetz et al. (Chem.-Ztg. 114:321-322 (1990)) describe a compound offormula:

Goerlitzer et al. (Arch. Pharm. (Weinheim, Ger.) 325:357-359 (1992))describe a compound of formula:

U.S. Pat. No. 5,389,632 describes the following compounds as reactants:

Goerlitzer et al. (Pharmazie 52:97-100 (1997)) describe the followingcompounds:

where Y is OMe or OEt.

Chambers et al. (Bioorg. Med. Chem. Lett. 7:739-744 (1997)) describe thefollowing compounds as useful in the treatment of rheumatoid arthritis:

Reddy et al. (Synth. Commun. 27:2217-2222 (1997)) describe the followingformula:

where Y is H or CF₃.

Rottlander et al. (Synlett (9):1084-1086 (1997)) describe3-(4-methoxyphenyl)pyridine-4-carboxamide.

Singh et al. (Indian J. Chem., Sect. B: Org Chem. Incl. Med. Chem.37B(5):517-520 (1998)) describe2-amino-4-n-butoxy-5-(4-methoxyphenyl)pyridine-3-carboxamide.

SUMMARY OF THE INVENTION

The present invention is related to the discovery that aryl substitutedpyridines represented by Formula I act as blockers of sodium (Na⁺)channels.

The invention is also related with treating a disorder responsive to theblockade of sodium channels in a mammal suffering from excess activityof said channels by administering an effective amount of a compound ofFormula I as described herein.

The present invention is also directed to the use of a compound ofFormula I for the treatment of neuronal damage following global andfocal ischemia, and for the treatment or prevention of neurodegenerativeconditions such as amyotrophic lateral sclerosis (ALS), for thetreatment of tinnitus, as antimanic depressants, as local anesthetics,as antiarrhythmics, as anticonvulsants and for the treatment orprevention of diabetic neuropathy and for the treatment of painincluding both acute and chronic pain and migraine headache.

A number of compounds useful in the present invention have not beenheretofor reported. Thus, one aspect of the present invention isdirected to the novel aryl substituted pyridines of Formula I.

Another aspect of the present invention is directed to the novelcompounds of Formula I as blockers of sodium channels.

A further aspect of the present invention is to provide a method fortreating, preventing or ameliorating neuronal loss following global andfocal ischemia; treating, preventing or ameliorating pain includingacute and chronic pain, and neuropathic pain; treating, preventing orameliorating convulsion and neurodegenerative conditions; treating,preventing or ameliorating manic depression; using as local anesthesicsand anti-arrhythmics, and treating tinnitus by administering a compoundof Formula I to a mammal in need of such treatment or use.

Also, an aspect of the present invention is to provide a pharmaceuticalcomposition useful for treating disorders responsive to the blockade ofsodium ion channels, containing an effective amount of a compound ofFormula I in a mixture with one or more pharmaceutically acceptablecarriers or diluents.

Further, the present invention is directed to ³H and ¹⁴C radiolabeledcompounds of Formula I and their use as radioligands for their bindingsite on the sodium channel.

Additional embodiments and advantages of the invention will be set forthin part in the description that follows, and in part will be obviousfrom the description, or may be learned by practice of the invention.The embodiments and advantages of the invention will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

The present invention arises out of the discovery that aryl substitutedpyridines of Formula I act as blockers of Na⁺ channels. In view of thisdiscovery compounds of Formula I are useful for treating disordersresponsive to the blockade of sodium ion channels.

The compounds useful in this aspect of the present invention are arylsubstituted pyridines represented by Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein:Ar is selected from the group consisting of Ar₁, Ar₂, Ar₃ and Ar₄,wherein

Ar₁ is

Ar₂ is

Ar₃ is

Ar₄ is

R₁ is selected from the group consisting of an optionally substitutedalkyl, amino, alkylthiol, C(O)R₁₀, SO₂R₁₀, OC(O)NH₂, 2-imidazolinyl,2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;

R₂, R₃, and R₄ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, alkenyl, or alkynyl, halogen,hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy,aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl,aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, andaralkylcarbonylamino;

provided that

-   -   1) the pyridyl ring is other than 2,6-disubstituted with regard        to Ar and R₁ or any of R₂-R₄ that is other than hydrogen; and    -   2) when Ar is Ar₂ or Ar₃, then R₁ is C(O)R₁₀;    -   3) when Ar is Ar₄, then R₁ is aminocarbonyl or an optionally        substituted heterocycloalkylaminocarbonyl;

R₅, R₆, R₇, and R₈ are independently selected from the group consistingof hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl,hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido andalkylthiol;

R₉ is an optionally substituted alkyl;

R₁₀ is selected from the group consisting of alkyl, alkenyl, alkynyl,OR₁₁, amino, alkylamino, dialkylamino, alkenylamino,dialkylaminoalkenyl, dialkylaminoalkylamino, dialkylaminoalkenylamino,alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl,heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl,arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of whichcan be optionally substituted, provided that R₁₀ is not OR₁₁ when R₁ isSO₂R₁₀; wherein

R₁₁ is selected from the group consisting of hydrogen, optionallysubstituted alkyl, and an alkali metal; and

X is one of O, S, NH, or CH₂ when Ar is Ar₁; or

X is one of O, S, NH, or absent (a covalent bond) when Ar is Ar₄.

Since the compounds of Formula I are blockers of sodium (Na⁺) channels,a number of diseases and conditions mediated by sodium ion influx can betreated employing these compounds. Therefore, the invention is relatedto a method of treating, preventing or ameliorating neuronal lossassociated with stroke, global and focal ischemia, CNS trauma,hypoglycemia and surgery, spinal cord trauma; as well as treating orameliorating neurodegenerative diseases including Alzheimer's disease,amyotrophic lateral sclerosis, Parkinson's disease, treating orameliorating anxiety, convulsions, glaucoma, migraine headache, andmuscle spasm. The compounds of Formula I are also useful as antitinnitusagents, antimanic depressants, as local anesthetics, and asantiarrhythmics; as well as for treating, preventing or amelioratingpain including surgical, chronic and neuropathic pain. In each instance,the methods of the present invention require administering to an animalin need of such treatment an effective amount of a sodium channelblocker of the present invention, or a pharmaceutically acceptable saltor prodrug thereof.

Accordingly, compounds useful in the present invention are arylsubstituted pyridines represented by Formula II:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein:

R₁ is selected from the group consisting of an optionally substitutedalkyl, amino, alkylthiol, C(O)R₁₀, SO₂R₁₀, OC(O)NH₂, 2-imidazolinyl,2-imidazolyl, 3-pyrazolyl, 5-isoxazolyl, and 3-(1,2,4)-triazolyl;

R₂, R₃, and R₄ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, alkenyl, or alkynyl, halogen,hydroxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxy,aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl,aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, andaralkylcarbonylamino;

provided that the pyridyl ring is other than 2,6-disubstituted withregard to the aryl radical and R₁ or any of R₂-R₄ that is other thanhydrogen;

R₅, R₆, R₇, and R₈ are independently selected from the group consistingof hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl,hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido andalkylthiol; and

R₁₀ is selected from the group consisting of alkyl, alkenyl, alkynyl,OR₁₁, amino, alkylamino, dialkylamino, alkenylamino,dialkylaminoalkenyl, dialkylaminoalkylamino, dialkylaminoalkenylamino,alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl,heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl,arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of whichcan be optionally substituted, provided that R₁₀ is not OR₁₁ when R₁ isSO₂R₁₀; wherein

R₁₁ is selected from the group consisting of hydrogen, optionallysubstituted alkyl, and an alkali metal; and

X is one of O, S, NH, or CH₂.

Another group of compounds useful in this aspect of the presentinvention are aryl substituted pyridines represented by the generalFormula II, wherein R₁-R₈ and R₁₀-R₁₁ are as described above, with theproviso that when X is O, R₅, R₆ and R₇ are each hydrogen, and R₁ is analkyl group, then R₈ is other than an optionally substituted alkoxygroup.

Preferably, R₁ is selected from the group consisting of an alkyloptionally substituted by halogen or hydroxy, thiomethyl, C(O)R₁₀,SO₂R₁₀, 2-imidazolinyl, 2-imidazolyl, 3-pyrazolyl, and 5-isoxazolyl,wherein R₁₀ is selected from the group consisting of alkyl, alkenyl,OR₁₁, amino, alkylamino, dialkylamino, alkenylamino,dialkylaminoalkenyl, dialkylaminoalkylamino, and heterocycloalkylamino,all of which can be optionally substituted, provided that R₁₀ is notOR₁₁ when R₁ is SO₂R₁₀.

Preferably, R₂, R₃ and R₄ are independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aminoalkyl, amino,hydroxyalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino,arylcarbonylamino, and aralkylcarbonylamino, more preferably hydrogen,alkyl, alkoxy, aminoalkyl and aminocarbonyl. Preferably both R₃ and R₄are hydrogen.

Preferably, R₅, R₆, R₇, and R₈ are independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, and cyano. More preferably, R₅, R₆,R₇ and R₈ are independently selected from the group consisting ofhydrogen, alkyl, halogen, haloalkyl, and nitro. Preferred values ofR₅-R₈ include hydrogen, halo, C₁-C₆ haloalkyl, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ hydroxyalkyl, nitro, amino, ureido, cyano,C₁-C₆ acylamido, hydroxy, thiol, C₁-C₆ acyloxy, azido, C₁-C₆ alkoxy, orcarboxy. The groups R₅-R₈ each take the place of a hydrogen atom thatwould otherwise be present in any position on the aryl ring to which theR group is attached. Especially preferred are compounds where R₅ and R₆are both hydrogen, R₇ is hydrogen and R₈ is a fluoro in thepara-position.

Preferably, R₉ is a branched alkyl group of C₃₋₁₀ carbon atoms, morepreferably C₃₋₆ carbon atoms, optionally substituted with one or more ofhalogen, hydroxy, nitro, amino, cyano, and alkoxy.

Preferably, R₁₀ is selected from the group consisting of alkyl, alkenyl,OR₁₁, amino, alkylamino, dialkylamino, alkenylamino,dialkylaminoalkenyl, dialkylaminoalkylamino, and heterocycloalkylamino,preferably piperidinylethylamino, all of which can be optionallysubstituted, wherein R₁₁ is as defined above, provided that R₁₀ is notOR₁₁ when R₁ is SO₂R₁₀.

Preferably X is O or S, more preferably X is O.

In one aspect of the invention, preferred compounds falling within thescope of Formula II include compounds wherein X is O or S. In thisaspect of the invention R₁ is preferably aminocarbonyl orheterocycloalkylaminocarbonyl, especially2-(N-piperidinyl)ethylamino-carbonyl, and R₂, R₃, and R₄ each arepreferably hydrogen. Preferred R₅-R₈ groups are as described above.

The invention also relates to aryl-substituted pyridines represented byFormula III:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein:

R₂-R₈, R₁₀ and X are defined previously with respect to Formulae I-II;

provided that the pyridyl ring is other than 2,6-disubstituted withregard to the aryl radical and —C(O)R₁₀ or any of R₂-R₄ that is otherthan hydrogen.

Preferred compounds falling within the scope of Formula III includecompounds wherein R₂, R₃, and R₄ are hydrogen, R₁₀ is amino, and X is Oand S. R₅ through R₈ have preferred values as described above forFormula II. Further, preferably R₁₀ is selected from the groupconsisting of alkyl, alkenyl, amino, alkylamino, dialkylamino,alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino, andheterocycloalkylamino, preferably 2-(N-piperidinyl)ethylamino, all ofwhich can be optionally substituted.

Further, compounds useful in the present invention are aryl substitutedpyridines represented by Formula IV:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein:

R₂-R₈ are defined previously with respect to Formulae I-III,

provided that the pyridyl ring is other than 2,6-disubstituted withregard to the naphthyl radical and —C(O)R₁₀ or any of R₂-R₄ that isother than hydrogen. R₂ through R₈ have preferred values as describedabove for Formula II. Preferably R₂-R₄ each are hydrogen.

Further, compounds useful in the present invention are aryl substitutedpyridines represented by Formula V:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein:

R₂-R₈ are defined previously with respect to Formulae I-III;

provided that the pyridyl ring is other than 2,6-disubstituted withregard to the biphenyl radical and —C(O)R₁₀ or any of R₂-R₄ that isother than hydrogen. R₂ through R₈ have preferred values as describedabove for Formula II. Preferably R₂-R₄ each are hydrogen.

Also, compounds useful in the present invention are aryl substitutedpyridines represented by Formula VI:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein:

R₅, R₆, and R₉ are defined previously with respect to Formulae I-II, Xis one of O, S, NH, or absent, and R₁₀ is amino orheterocycloalkylamino;

provided that the pyridyl ring is other than 2,6-disubstituted withregard to the phenyl radical and —C(O)R₁₀.

Another group of compounds useful in this aspect of the presentinvention are aryl substituted pyridines represented by the generalFormula VI, wherein R₅, R₆, R₉, and X are as described above, and R₂-R₄each are hydrogen, with the proviso that when X is O or absent and R₁₀is amino, then R₉ is not a straight chain alkyl group optionallymono-substituted with halogen, carboxy, alkoxy, an optionallysubstituted phenyl, or an optionally substituted aminocarbonyl.

Preferred compounds falling within the scope of Formula VI includecompounds wherein X is O, S, or absent. Preferably, R₉ is a branchedchain C₃₋₆ alkyl, more preferably C₃₋₄ alkyl, optionally substitutedwith one or more of halogen, especially fluoro or chloro, ortrihalomethyl, especially trifluoromethyl. R₅ and R₆ have preferredvalues as described above for Formula II.

Exemplary preferred compounds that may be employed in this method ofinvention include, without limitation:

-   2-[4-(4-fluorophenoxy)phenyl]pyridine-3-carboxamide;-   2-[4-(4-fluorophenoxy)phenyl]pyridine-4-carboxamide;-   2-(4-phenoxyphenyl)pyridine-5-carboxamide;-   2-(4-phenoxyphenyl)pyridine-4-carboxamide;-   5-(4-phenoxyphenyl)pyridine-3-carboxamide-   2-[4-(4-fluorophenoxy)phenyl]pyridine 5-carboxylic acid    2-(N-piperidinyl)ethylamide; and-   5-[4-(4-fluorophenoxy)phenyl]pyridine 3-carboxylic acid    2-(N-piperidinyl)ethylamide;

or a pharmaceutically acceptable salt, prodrug or solvate thereof.

Additional useful compounds of the present invention include:

-   5-(2-naphthyl)pyridine-3-carboxamide;-   2-(2-naphthyl)pyridine-5-carboxamide;-   2-(4-phenylphenyl)pyridine-4-carboxamide; and-   2-(4-phenylphenyl)pyridine-5-carboxamide;

or a pharmaceutically acceptable salt, prodrug or solvate thereof.

Further useful compounds of the invention include:

-   5-(4-tert-butylphenyl)pyridine-3-carboxamide;-   2-(4-tert-butylphenyl)pyridine-4-carboxamide;-   2-(4-tert-butylphenyl)pyridine-5-carboxamide-   2-(4-i-propylphenyl)pyridine-4-carboxamide;-   5-(4-thiomethylphenyl)pyridine-3-carboxamide;-   2-(4-thiomethylphenyl)pyridine-5-carboxamide;-   5-(4-trifluoromethoxyphenyl)pyridine-3-carboxamide;-   2-(4-trifluoromethoxyphenyl)pyridine-5-carboxamide;-   2-(4-trifluoromethoxyphenyl)pyridine-4-carboxamide;-   5-(4-trifluoromethylphenyl)pyridine-3-carboxamide; and-   2-(4-trifluoromethylphenyl)pyridine-5-carboxamide;

or a pharmaceutically acceptable salt, prodrug or solvate thereof.

Further compounds that may be employed in this method of inventioninclude:

-   2-(4-n-butylphenyl)pyridine-4-carboxamide;-   2-(4-methoxyphenyl)pyridine-4-carboxamide;-   2-(4-ethoxyphenyl)pyridine-4-carboxamide;-   5-(4-ethoxyphenyl)pyridine-3-carboxamide;-   5-(4-methoxyphenyl)pyridine-3-carboxamide;-   5-(4-n-butylphenyl)pyridine-3-carboxamide;-   2-(4-ethoxyphenyl)pyridine-5-carboxamide;-   2-(4-methoxyphenyl)pyridine-5-carboxamide;-   2-(4-n-butylphenyl)pyridine-5-carboxamide;

or a pharmaceutically acceptable salt, prodrug or solvate thereof.

Useful aryl groups are C₆₋₁₄ aryl, especially C₆₋₁₀ aryl. Typical C₆₋₁₄aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl,azulenyl, biphenyl, biphenylenyl and fluorenyl groups.

Useful cycloalkyl groups are C₃₋₈ cycloalkyl. Typical cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

Useful halo or halogen groups include fluorine, chlorine, bromine andiodine.

Useful alkyl groups include straight-chained and branched C₁₋₁₀ alkylgroups, more preferably C₁₋₆ alkyl groups. Typical C₁₋₁₀ alkyl groupsinclude methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,3-pentyl, hexyl and octyl groups. Also contemplated is a trimethylenegroup substituted on two adjoining positions on the benzene ring of thecompounds of the invention.

Useful alkenyl groups are C₂₋₆ alkenyl groups, preferably C₂₋₄ alkenyl.Typical C₂₋₄ alkenyl groups include ethenyl, propenyl, isopropenyl,butenyl, and sec-butenyl.

Useful alkynyl groups are C₂₋₆ alkynyl groups, preferably C₂₋₄ alkynyl.Typical C₂₋₄ alkynyl groups include ethynyl, propynyl, butynyl, and2-butynyl groups.

Useful arylalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by any of the above-mentioned C₆₋₁₄ aryl groups.Useful values include benzyl, phenethyl and naphthylmethyl.

Useful arylalkenyl groups include any of the above-mentioned C₂₋₄alkenyl groups substituted by any of the above-mentioned C₆₋₁₄ arylgroups.

Useful arylalkynyl groups include any of the above-mentioned C₂₋₄alkynyl groups substituted by any of the above-mentioned C₆₋₁₄ arylgroups. Useful values include phenylethynyl and phenylpropynyl.

Useful cycloalkylalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned cycloalkylgroups.

Useful haloalkyl groups include C₁₋₁₀ alkyl groups substituted by one ormore fluorine, chlorine, bromine or iodine atoms, e.g. fluoromethyl,difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl andtrichloromethyl groups.

Useful hydroxyalkyl groups include C₁₋₁₀ alkyl groups substituted byhydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl andhydroxybutyl groups.

Useful alkoxy groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above.

Useful alkylthio groups include sulfur substituted by one of the C₁₋₁₀alkyl groups mentioned above.

Useful acylamino groups are any acyl group, particularly C₂₋₆ alkanoylor C₆₋₁₀ aryl(C₂₋₆)alkanoyl attached to an amino nitrogen, e.g.acetamido, propionamido, butanoylamido, pentanoylamido, hexanoylamido,and benzoyl.

Useful acyloxy groups are any C₁₋₆ acyl (alkanoyl) attached to an oxy(—O—) group, e.g. acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy,hexanoyloxy and the like.

The term heterocyclic is used herein to mean saturated or wholly orpartially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclicring system, which consists of carbon atoms and from one to fourheteroatoms independently selected from the group consisting of O, N,and S, wherein the nitrogen and sulfur heteroatoms can be optionallyoxidized, the nitrogen can be optionally quaternized, and including anybicyclic group in which any of the above-defined heterocyclic rings isfused to a benzene ring, and wherein the heterocyclic ring can besubstituted on carbon or on a nitrogen atom if the resulting compound isstable. Examples include, but are not limited to, pyrrolidine,piperidine, piperazine, morpholine, imidazoline, pyrazolidine,benzodiazepines, and the like.

Useful heterocycloalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned heterocyclicgroups.

Useful heterocycloalkylamino groups include any of the above-mentionedheterocycloalkyl groups attached to an amino nitrogen, such asN-piperidinylethylamino, especially, 2-(N-piperidinyl)ethylamino.

Useful alkylamino and dialkylamino groups are —NHR₁₂ and —NR₁₂R₁₃,wherein R₁₂ and R₁₃ are C₁₋₁₀ alkyl groups.

Useful dialkylaminoalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned dialkylaminogroups.

Useful dialkylaminoalkylamino groups include any of the above-mentioneddialkylaminoalkyl groups attached to an amino nitrogen, such asdimethylaminoethylamino.

Aminocarbonyl group is —C(O)NH₂.

Useful alkylaminocarbonyl groups are carbonyl groups substituted by—NHR₁₂ and —NR₁₂R₁₃, wherein R₁₂ and R₁₃ are C₁₋₁₀ alkyl groups.

Useful alkylthiol groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by a —SH group.

A carboxy group is —COOH.

An azido group is —N₃.

An ureido group is —NH—C(O)—NH₂.

An amino group is —NH₂.

An amide group is an organic radical having —NHC(O)— as a functionalgroup.

Optional substituents on R₁-R₁₁ include any one of halo, halo(C₁₋₆)alkyl, aryl, heterocycle, cycloalkyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl(C₁₋₆)alkyl, aryl(C₂₋₆)alkenyl, aryl(C₂₋₆)alkynyl,cycloalkyl(C₁₋₆)alkyl, heterocyclo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,amino(C₁₋₆)alkyl, carboxy(C₁₋₆)alkyl, alkoxy(C₁₋₆)alkyl, nitro, amino,ureido, cyano, acylamino, hydroxy, thiol, acyloxy, azido, alkoxy,carboxy, aminocarbonyl, and C₁₋₆ alkylthiol groups mentioned above.Preferred optional substituents include: halo, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, hydroxy, nitro, C₁₋₆ alkyl, alkoxyand amino.

The invention disclosed herein is also meant to encompass prodrugs ofthe disclosed compounds. Prodrugs are considered to be any covalentlybonded carriers which release the active parent drug in vivo.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfor example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled compound of the invention, administering it parenterallyin a detectable dose to an animal such as rat, mouse, guinea pig,monkey, or to man, allowing sufficient time for metabolism to occur andisolating its conversion products from the urine, blood or otherbiological samples.

The invention disclosed herein is also meant to encompass the disclosedcompounds being isotopically-labelled by having one or more atomsreplaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Some of the compounds disclosed herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The present invention is also meant toencompass all such possible forms, as well as their racemic and resolvedforms and mixtures thereof. The individual enantiomers may be separatedaccording to methods that are well known to those of ordinary skill inthe art. When the compounds described herein contain olefinic doublebonds or other centers of geometric asymmetry, and unless specifiedotherwise, it is intended to include both E and Z geometric isomers. Alltautomers are intended to be encompassed by the present invention aswell.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposeable on its mirror image and hence optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image rotates the plane of polarized light inthe opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The invention disclosed is also meant to encompass all pharmaceuticallyacceptable salts thereof of the disclosed compounds. Examples ofpharmaceutically acceptable addition salts include inorganic and organicacid addition salts. The pharmaceutically acceptable salts include, butare not limited to, metal salts such as sodium salt, potassium salt,cesium salt and the like; alkaline earth metals such as calcium salt,magnesium salt and the like; organic amine salts such as triethylaminesalt, pyridine salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and thelike; inorganic acid salts such as hydrochloride, hydrobromide,phosphate, sulphate and the like; organic acid salts such as citrate,lactate, tartrate, maleate, fumarate, mandelate, acetate,dichloroacetate, trifluoroacetate, oxalate, formate and the like;sulfonates such as methanesulfonate, benzenesulfonate,p-toluenesulfonate and the like; and amino acid salts such as arginate,asparginate, glutamate and the like.

Examples of prodrugs include esters or amides of Formulae I-VI with anyof R₂-R₈ as hydroxyalkyl or aminoalkyl, and these may be prepared byreacting such compounds with anhydrides such as succinic anhydride.

The invention is also directed to a method for treating disordersresponsive to the blockade of sodium channels in animals sufferingthereof. Particular preferred embodiments of the aryl substitutedpyridyl compounds for use in method of this invention are represented bypreviously defined Formulae I-VI.

The compounds of this invention may be prepared using methods known tothose skilled in the art. For example, 2,5-disubstituted pyridine amidescan be prepared according to Scheme 1 as follows:

Further, 3,5-disubstituted pyridine amides can be prepared according toScheme 2 as follows:

2,4-Disubstituted pyridine amides can be prepared, for example, asfollows in Scheme 3:

wherein R is, e.g., OPh, tert-butyl, Ph, n-butyl, i-Pr, OCF₃, OMe orOEt.

2,3-Distributed pyridine amides can be prepared, for example, as shownin Scheme 4.

The invention is also directed to ³H and ¹⁴C radiolabeled compounds ofFormula I and their use as radioligands for their binding site on thesodium channel. For example, one use of the labeled compounds of theinvention is the characterization of specific receptor binding. Anotheruse of the labeled compounds of the invention is an alternative toanimal testing for the evaluation of structure-activity relationships.The receptor assay is performed at a fixed concentration of a labeledcompound of Formula I and at increasing concentrations of a testcompound in a competition assay.

Tritiated compounds of Formula I can be prepared by introducing tritiuminto the compound of Formula I by, for example, catalytic dehalogenationwith tritium. This method includes reacting a suitablyhalogen-substituted precursor of a compound of Formula I with tritiumgas in the presence of a suitable catalyst, for example Pd/C, in thepresence or absence of a base. Other suitable methods for preparingtritiated compounds can be found in Filer, Isotopes in the Physical andBiomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6.¹⁴C-labeled compounds can be prepared by employing starting materialshaving a ¹⁴C carbon.

The compounds of the present invention were assessed byelectrophysiological assays in dissociated hippocampal neurons forsodium channel blocker activity. These compounds also could be assayedfor binding to the neuronal voltage-dependent sodium channel using ratforebrain membranes and [³H]BTX-B.

Sodium channels are large transmembrane proteins that are expressed invarious tissues. They are voltage sensitive channels and are responsiblefor the rapid increase of Na⁺ permeability in response to depolarizationassociated with the action potential in many excitable cells includingmuscle, nerve and cardiac cells.

One aspect of the present invention is the discovery of the mechanism ofaction of the compounds herein described as specific Na⁺ channelblockers. Based upon the discovery of this mechanism, these compoundsare contemplated to be useful in treating or preventing neuronal lossdue to focal or global ischemia, and in treating or preventingneurodegenerative disorders including ALS, anxiety, and epilepsy. Theyare also expected to be effective in treating, preventing orameliorating neuropathic pain, surgical pain, chronic pain and tinnitus.The compounds are also expected to be useful as antiarrhythmics,anesthetics and antimanic depressants.

The present invention is directed to compounds of Formulae I-VI that areblockers of voltage-sensitive sodium channels. According to the presentinvention, those compounds having preferred sodium channel blockingproperties exhibit an IC₅₀ of about 100 μM or less in theelectrophysiological assay described herein. Preferably, the compoundsof the present invention exhibit an IC₅₀ of 10 μM or less. Mostpreferably, the compounds of the present invention exhibit an IC₅₀ ofabout 1.0 μM or less. Substituted heteroaryl compounds of the presentinvention may be tested for their Na⁺ channel blocking activity by thefollowing electrophysiological and binding assays.

Electrophysiological Assay:

Electrophysiological Assay was used to measure potencies of compounds ofthe present invention rBIIa/beta 1 sodium channels expressed in Xenopusoocytes.

Preparation of cRNA encoding cloned rat brain type IIa (rBIIa) and beta1 (β1): cDNA clones encoding the rat brain beta 1 subunit were cloned inhouse using standard methods, and mRNA were prepared by standardmethods. mRNA encoding rBIIa was provided by Dr. A. Golden (UC Irvine).The mRNAs were diluted and stored at −80° C. in 1 μL aliquots untilinjection.

Preparation of oocytes: Mature female Xenopus laevis were anaesthetized(20-40 min) using 0.15% 3-aminobenzoic acid ethyl ester (MS-222)following established procedures (Woodward, R. M., et al., Mol.Pharmacol. 41:89-103 (1992)).

Two to six ovarian lobes were surgically removed. Oocytes atdevelopmental stages V-VI were dissected from the ovary, oocytes werestill surrounded by enveloping ovarian tissues. Oocytes weredefolliculated on the day of surgery by treatment with collagenase (0.5mg/mL Sigma Type I, or Boehringer Mannheim Type A, for 0.5-1 hr).Treated oocytes were vortexed to dislodge epithelia, washed repeatedlyand stored in Barth's medium containing 88 mM NaCl, 1 mM KCl, 0.41 mMCaCl₂, 0.33 mM Ca(NO₃)₂, 0.82 mM MgSO₄, 2.4 mM NaHCO₃, 5 mM HEPES, pH7.4 adjusted with 0.1 mg/mL gentamycin sulphate.

Micro-injection of oocytes: Defolliculated oocytes were micro-injectedusing a Nanoject injection system (Drummond Scientific Co., Broomall,Pa.). Injection pipettes were beveled to minimize clogging. Tip diameterof injection pipettes was 15-35 μm. Oocytes were microinjected withapproximately 50 nL 1:10 ratio mixtures of cRNAs for rBIIa and beta 1respectively.

Electrophysiology: Membrane current responses were recorded in frogRinger solution containing 115 mM NaCl, 2 mM KCl, 1.8 mM CaCl₂, 5 mMHEPES, pH 7.4. Electrical recordings were made using a conventionaltwo-electrode voltage clamp (Dagan TEV-200) over periods ranging between1-7 days following injection. The recording chamber was a simple gravityfed flow-through chamber (volume 100-500 mL depending on adjustment ofaspirator). Oocytes were placed in the recording chamber, impaled withelectrodes and continuously perfused (5-15 mL min⁻¹) with frog Ringer'ssolution. The tested compounds were applied by bath perfusion.

Voltage protocols for evoking sodium channel currents: The standardholding potential for whole oocyte clamp was −120 mV. Standardcurrent-voltage relationships were elicited by 40 ms depolarizing stepsstarting from −60 mV to +50 mV in 10 mV increments. Peak currents weremeasured as the maximum negative current after depolarizing voltagesteps. The voltage from maximum current response was noted and used forthe next voltage protocol.

The purpose was to find compounds that are state dependent modifiers ofneuronal sodium channels. Preferably, the compounds have a low affinityfor the rested/closed state of the channel, but a high affinity for theinactivated state. The following voltage protocol was used to measure acompounds affinity for the inactivated state. Oocytes were held at aholding potential of −120 mV. At this membrane voltage, nearly all ofthe channels would be in the closed state. Then a 4 seconddepolarization was made to the voltage where the maximum current waselicited. At the end of this depolarization, nearly all the channelswould be in the inactivated state. A 10 ms hyperpolarizing step was thenmade in order to remove some channels from the inactivated state. Afinal depolarizing test pulse was used to assay the sodium current afterthis prolonged depolarization (see analysis below). Sodium currents weremeasured at this test pulse before and after the application of thetested compound. Data was acquired using pClamp 8.0 software andanalyzed with clampfit software (Axon instruments).

Data analysis: Apparent inhibition constants (K_(i) values) forantagonists were determined from single point inhibition data using thefollowing equation (a generalized form of the Cheng-Prusoff equation)(Leff, P. and I. G. Dougall, TiPS 14:110-112 (1993)).K _(i)=(FR/1−FR)*[drug]  Eq. 1Where FR is the fractional response and is defined as sodium currentelicited from the final depolarizing test pulse prior to application ofthe drug divided by the sodium current measured in the presence of thedrug. [drug] is the concentration of the drug used.

Drugs: Drugs were initially made up at concentrations of 2-10 mM inDMSO. Dilutions were then made to generate a series of DMSO stocks overthe range 0.3 μM to 10 mM—depending upon the potency of the compound.Working solutions were made by 1000-3000 fold dilution of stocks intoRinger. At these dilutions DMSO alone had little or no measurableeffects on membrane current responses. DMSO stocks of drugs were storedin the dark at 4° C. Ringer solutions of drugs were made up fresh eachday of use.

In Vitro Binding Assay:

The ability of compounds of the present invention to modulate eithersite 1 or site 2 of the Na⁺ channel was determined following theprocedures fully described in Yasushi, J. Biol. Chem. 261:6149-6152(1986) and Creveling, Mol. Pharmacol. 23:350-358 (1983), respectively.Rat forebrain membranes were used as sources of Na⁺ channel proteins.The binding assays were conducted in 130 μM choline chloride at 37° C.for 60-minute incubation with [³H] saxitoxin and [³H] batrachotoxin asradioligands for site 1 and site 2, respectively.

In Vivo Pharmacology:

The compounds of the present invention may be tested for in vivoanticonvulsant activity after i.v., p.o. or i.p. injection using anumber of anticonvulsant tests in mice, including the maximumelectroshock seizure test (MES). Maximum electroshock seizures wereinduced in male NSA mice weighing between 15-20 g and maleSprague-Dawley rats weighing between 200-225 g by application of current(50 mA, 60 pulses/sec, 0.8 msec pulse width, 1 sec duration, D.C., mice;99 mA, 125 pulses/sec, 0.8 msec pulse width, 2 sec duration, D.C., rats)using a Ugo Basile ECT device (Model 7801). Mice were restrained bygripping the loose skin on their dorsal surface and saline-coatedcorneal electrodes were held lightly against the two corneae. Rats wereallowed free movement on the bench top and ear-clip electrodes wereused. Current was applied and animals were observed for a period of upto 30 seconds for the occurrence of a tonic hindlimb extensor response.A tonic seizure was defined as a hindlimb extension in excess of 90degrees from the plane of the body. Results were treated in a quantalmanner.

The compounds may be tested for their antinociceptive activity in theformalin model as described in Hunskaar, S., O. B. Fasmer, and K. Hole,J. Neurosci. Methods 14: 69-76 (1985). Male Swiss Webster NIH mice(20-30 g; Harlan, San Diego, Calif.) were used in all experiments. Foodwas withdrawn on the day of experiment. Mice were placed in Plexiglassjars for at least 1 hour to accommodate to the environment. Followingthe accommodation period mice were weighed and given either the compoundof interest administered i.p. or p.o., or the appropriate volume ofvehicle (10% Tween-80). Fifteen minutes after the i.p. dosing, and 30minutes after the p.o. dosing mice were injected with formalin (20 μL of5% formaldehyde solution in saline) into the dorsal surface of the righthind paw. Mice were transferred to the Plexiglass jars and monitored forthe amount of time spent licking or biting the injected paw. Periods oflicking and biting were recorded in 5 minute intervals for 1 hour afterthe formalin injection. All experiments were done in a blinded mannerduring the light cycle. The early phase of the formalin response wasmeasured as licking/biting between 0-5 minutes, and the late phase wasmeasured from 15-50 minutes. Differences between vehicle and drugtreated groups were analyzed by one-way analysis of variance (ANOVA). AP value ≦0.05 was considered significant. Having activity in blockingthe acute and second phase of formalin-induced paw-licking activity, thecompounds are considered to be efficacious for acute and chronic pain.

The compounds may be tested for their potential for the treatment ofchronic pain (antiallodynic and antihyperalgesic activities) in theChung model of peripheral neuropathy. Male Sprague-Dawley rats weighingbetween 200-225 g were anesthetized with halothane (1-3% in a mixture of70% air and 30% oxygen) and their body temperature controlled duringanesthesia through use of a homeothermic blanket. A 2-cm dorsal midlineincision was then made at the L5 and L6 level and the para-vertibralmuscle groups retracted bilaterally. L5 and L6 spinal nerves were thenbe exposed, isolated, and tightly ligated with 6-0 silk suture. A shamoperation was performed exposing the contralateral L5 and L6 spinalnerves as a negative control.

Tactile Allodynia. Rats were transferred to an elevated testing cagewith a wire mesh floor and allowed to acclimate for five to ten minutes.A series of Semmes-Weinstein monofilaments were applied to the plantarsurface of the hindpaw to determine the animal's withdrawal threshold.The first filament used possessed a buckling weight of 9.1 gms (0.96 logvalue) and was applied up to five times to see if it elicited awithdrawal response. If the animal had a withdrawal response then thenext lightest filament in the series would be applied up to five timesto determine if it could elicit a response. This procedure was repeatedwith subsequent lesser filaments until there was no response and thelightest filament that elicited a response was recorded. If the animaldid not have a withdrawal response from the initial 9.1 gms filamentthen subsequent filaments of increased weight were applied until afilament elicited a response and this filament was then recorded. Foreach animal, three measurements were made at every time point to producean average withdrawal threshold determination. Tests were performedprior to and at 1, 2, 4 and 24 hours post drug administration. Tactileallodynia and mechanical hyperalgesia tests were conducted concurrently.

Mechanical Hyperalgesia. Rats were transferred to an elevated testingcage with a wire mesh floor and allowed to acclimate for five to tenminutes. A slightly blunted needle was touched to the plantar surface ofthe hindpaw causing a dimpling of the skin without penetrating the skin.Administration of the needle to control paws typically produced a quickflinching reaction, too short to be timed with a stopwatch andarbitrarily given a withdrawal time of 0.5 second. The operated side pawof neuropathic animals exhibited an exaggerated withdrawal response tothe blunted needle. A maximum withdrawal time of ten seconds was used asa cutoff time. Withdrawal times for both paws of the animals weremeasured three times at each time point with a five-minute recoveryperiod between applications. The three measures were used to generate anaverage withdrawal time for each time point. Tactile allodynia andmechanical hyperalgesia tests were conducted concurrently.

The compounds may be tested for their neuroprotective activity afterfocal and global ischemia produced in rats or gerbils according to theprocedures described in Buchan et al. (Stroke, Suppl. 148-152 (1993))and Sheardown et al. (Eur. J Pharmacol. 236:347-353 (1993)) and Grahamet al. (J. Pharmacol. Exp. Therap. 276:1-4 (1996)).

The compounds may be tested for their neuroprotective activity aftertraumatic spinal cord injury according to the procedures described inWrathall et al. (Exp. Neurology 137:119-126 (1996)) and Iwasaki et al.(J. Neuro Sci. 134:21-25 (1995)).

Compositions within the scope of this invention include all compositionswherein the compounds of the present invention are contained in anamount that is effective to achieve its intended purpose. Whileindividual needs vary, determination of optimal ranges of effectiveamounts of each component is within the skill of the art. Typically, thecompounds may be administered to mammals, e.g. humans, orally at a doseof 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceuticallyacceptable salt thereof, per day of the body weight of the mammal beingtreated for epilepsy, neurodegenerative diseases, anesthetic,arrhythmia, manic depression, and pain. For intramuscular injection, thedose is generally about one-half of the oral dose.

In the method of treatment or prevention of neuronal loss in global andfocal ischemia, brain and spinal cord trauma, hypoxia, hypoglycemia,status epilepsy and surgery, the compound can be administrated byintravenous injection at a dose of about 0.025 to about 10 mg/kg.

The unit oral dose may comprise from about 0.01 to about 50 mg,preferably about 0.1 to about 10 mg of the compound. The unit dose maybe administered one or more times daily as one or more tablets eachcontaining from about 0.1 to about 10, conveniently about 0.25 to 50 mgof the compound or its solvates.

In addition to administering the compound as a raw chemical, thecompounds of the invention may be administered as part of apharmaceutical preparation containing suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries whichfacilitate processing of the compounds into preparations which can beused pharmaceutically. Preferably, the preparations, particularly thosepreparations which can be administered orally and which can be used forthe preferred type of administration, such as tablets, dragees, andcapsules, and also preparations which can be administered rectally, suchas suppositories, as well as suitable solutions for administration byinjection or orally, contain from about 0.01 to 99 percent, preferablyfrom about 0.25 to 75 percent of active compound(s), together with theexcipient.

Also included within the scope of the present invention are thenon-toxic pharmaceutically acceptable salts of the compounds of thepresent invention. Acid addition salts are formed by mixing a solutionof the particular heteroaryl compound of the present invention with asolution of a pharmaceutically acceptable non-toxic acid such ashydrochloric acid, fumaric acid, maleic acid, succinic acid, aceticacid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalicacid, dichloroacetic acid, and the like. Basic salts are formed bymixing a solution of the heteroaryl compound of the present inventionwith a solution of a pharmaceutically acceptable non-toxic base such assodium hydroxide, potassium hydroxide, choline hydroxide, sodiumcarbonate and the like.

The pharmaceutical compositions of the invention may be administered toany animal that may experience the beneficial effects of the compoundsof the invention. Foremost among such animals are mammals, e.g., humans,although the invention is not intended to be so limited.

The pharmaceutical compositions of the present invention may beadministered by any means that achieve their intended purpose. Forexample, administration may be by parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, or buccal routes.Alternatively, or concurrently, administration may be by the oral route.The dosage administered will be dependent upon the age, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired.

The pharmaceutical preparations of the present invention aremanufactured in a manner which is itself known, for example, by means ofconventional mixing, granulating, dragee-making, dissolving, orlyophilizing processes. Thus, pharmaceutical preparations for oral usecan be obtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients are, in particular, fillers such as saccharides, forexample lactose or sucrose, mannitol or sorbitol, cellulose preparationsand/or calcium phosphates, for example tricalcium phosphate or calciumhydrogen phosphate, as well as binders such as starch paste, using, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose,sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,disintegrating agents may be added such as the above-mentioned starchesand also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar,or alginic acid or a salt thereof, such as sodium alginate. Auxiliariesare, above all, flow-regulating agents and lubricants, for example,silica, talc, stearic acid or salts thereof, such as magnesium stearateor calcium stearate, and/or polyethylene glycol. Dragee cores areprovided with suitable coatings that, if desired, are resistant togastric juices. For this purpose, concentrated saccharide solutions maybe used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, poly-ethylene glycol and/or titanium dioxide, lacquersolutions and suitable organic solvents or solvent mixtures. In order toproduce coatings resistant to gastric juices, solutions of suitablecellulose preparations such as acetylcellulose phthalate orhydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or pigmentsmay be added to the tablets or dragee coatings, for example, foridentification or in order to characterize combinations of activecompound doses.

Other pharmaceutical preparations which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain the active compounds in the form of granules whichmay be mixed with fillers such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds are preferablydissolved or suspended in suitable liquids, such as fatty oils, orliquid paraffin. In addition, stabilizers may be added.

Possible pharmaceutical preparations, which can be used rectally,include, for example, suppositories, which consist of a combination ofone or more of the active compounds with a suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,or paraffin hydrocarbons. In addition, it is also possible to usegelatin rectal capsules which consist of a combination of the activecompounds with a base. Possible base materials include, for example,liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts and alkaline solutions. In addition, suspensions ofthe active compounds as appropriate oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, for example, sesame oil, or synthetic fatty acid esters, forexample, ethyl oleate or triglycerides or polyethylene glycol-400 (thecompounds are soluble in PEG-400). Aqueous injection suspensions maycontain substances which increase the viscosity of the suspension, andinclude, for example, sodium carboxymethyl cellulose, sorbitol, and/ordextran. Optionally, the suspension may also contain stabilizers.

The following examples are illustrative, but not limiting, of the methodand compositions of the present invention. Other suitable modificationsand adaptations of the variety of conditions and parameters normallyencountered in clinical therapy and which are obvious to those skilledin the art are within the spirit and scope of the invention.

Example 1 2-[4-(4-Fluorophenoxy)phenyl]pyridine 5-carboxylic acid2-(N-piperidinyl)ethylamide (3)

a) 2-Chloropyridine-5-carboxylic acid 2-(N-piperidinyl)-ethylamide (2):To a solution of 6-chloronicotinic acid (1) (3.9 g, 24.8 mmol) and1-(2-aminoethyl)-piperidine (3.3 g, 26.0 mmol) in DMF was addedN-hydroxybenzotriazole (HOBt) (3.4 g, 24.8 mmol) and5-(3,4-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide (DIC) (3.1 g,24.8 mmol). The reaction mixture was allowed to stir 24 hours at ambienttemperature. The reaction mixture was diluted with dichloromethane, andwater was then added. The phases were separated, and the aqueous phasewas extracted twice with dichloromethane. The combined organic phaseswere dried over sodium sulfate. The solution was filtered andconcentrated to give compound 2 as a pale-yellow solid. Purification ofcompound 2 was then carried out by silica gel chromatography.

b) 2-[4-(4-Fluorophenoxy)phenyl]pyridine 5-carboxylic acid2-(N-piperidinyl)ethylamide (3): To a solution of compound 2 (536 mg,2.0 mmol) in 1,2-dimethoxyethane (6 mL) was added4-(4-fluorophenoxy)phenyl boronic acid (557 mg, 2.4 mmol), followed bywater (2 mL) and potassium carbonate (746 mg, 5.4 mmol). Pd(PPh₃)₄ (92mg, 0.08 mmol) was added to this mixture and the reaction mixture washeated at 85° C. for 16 hours under an argon atmosphere. The reactionmixture was allowed to return to ambient temperature, and the phaseswere separated. The aqueous phase was extracted three times with ethylacetate, and the combined organic phases were dried over sodium sulfate.The solution was filtered, concentrated, and then filtered over a bed offlorisil to give crude compound 3. Purification of compound 3 was thencarried out by silica gel chromatography. ¹H NMR (400 MHz, CDCl₃): δ1.27 (bs, 2H), 1.50-1.66 (m, 4H), 2.48 (bs, 4H), 2.61 (t, 2H, J=6.0 Hz),3.58 (t, 2H, J=5.8 Hz), 7.04-7.11 (m, 6H), 7.21 (bs, 1H), 7.78 (d, 1H,J=8.3 Hz), 8.03 (d, 2H, J=8.8 Hz), 8.22 (d, 1H, J=8.3 Hz), 9.04 (s, 1H).

The following compound was prepared similarly except that5-bromonicotinic acid was used instead of 6-chloronicotinic acid in stepa):

5-[4-(4-fluorophenoxy)phenyl]pyridine 3-carboxylic acid2-(N-piperidinyl)ethylamide (6): ¹H NMR (400 MHz, CDCl₃): δ 1.48 (bs,2H), 1.59-1.64 (m, 4H), 2.47 (bs, 4H), 2.60 (t, 2H, J=6.1 Hz), 3.58 (t,2H, J=5.7 Hz), 7.03-7.11 (m, 6H), 7.32 (bs, 1H), 7.59 (d, 2H, J=8.6 Hz),8.35 (t, 1H, J=2.2 Hz), 8.92 (d, 2H, J=2.1 Hz).

Example 2 2-(4-Phenoxyphenyl)pyridine-4-carboxamide (8a)2-(4-tert-Butylphenyl)pyridine-4-carboxamide (8b)2-(4-Phenylphenyl)pyridine-4-carboxamide (8c)2-(4-n-Butylphenyl)pyridine-4-carboxamide (8d)2-(4-i-Propylphenyl)pyridine-4-carboxamide (8e)2-(4-Trifluoromethoxyphenyl)pyridine-4-carboxamide (8f)2-(4-Methoxyphenyl)pyridine-4-carboxamide (8g)2-(4-Ethoxyphenyl)pyridine-4-carboxamide (8h)

Compounds 8a-8h: To a solution of compound 7 (536 mg, 2.0 mmol) in1,2-dimethoxyethane (6 mL) was added the appropriate phenyl boronic acid(2.4 mmol), followed by water (2 mL) and potassium carbonate (746 mg,5.4 mmol). Pd(PPh₃)₄ (92 mg, 0.08 mmol) was added to this mixture, andthe reaction mixture was heated at 85° C. for 16 hours under an argonatmosphere. The reaction mixture was allowed to return to ambienttemperature, and the phases were separated. The aqueous phase wasextracted three times with ethyl acetate, and the combined organicphases were dried over sodium sulfate. The solution was filtered,concentrated, and then filtered over a bed of florisil to give crudecompounds 8a-8h. Purification of compounds 8a-8h was then carried out bysilica gel chromatography.

2-(4-Phenoxyphenyl)pyridine-4-carboxamide (8a): ¹H NMR (400 MHz, CD₃OD):δ 7.03-7.15 (m, 5H), 7.33-7.41 (m, 2H), 7.62 (d, 1H, J=5.1 Hz), 7.95 (d,2H, J=8.7 Hz), 8.14 (s, 1H), 8.69 (d, 1H, J=5.1 Hz).

2-(4-tert-Butylphenyl)pyridine-4-carboxamide (8b): ¹H NMR (400 MHz,CD₃OD): δ 1.41 (s, 9H), 7.57 (d, 2H, J=8.6 Hz), 7.66 (dd, 1H, J=1.6, 5.1Hz), 7.98 (d, 2H, J=8.6 Hz), 8.20-8.21 (m, 1H), 8.77-8.78 (m, 1H).

2-(4-Phenylphenyl)pyridine-4-carboxamide (8c): ¹H NMR (400 MHz, CD₃OD):δ 7.35-7.48 (m, 4H), 7.64-7.75 (m, 5H), 8.08 (d, 2H, J=8.4 Hz), 8.25 (s,1H), 8.75 (d, 1H, J=5.2 Hz).

2-(4-n-Butylphenyl)pyridine-4-carboxamide (8d): ¹H NMR (400 MHz, CD₃OD):δ 0.95 (t, 3H, J=7.3 Hz), 1.37-1.42 (m, 2H), 1.62-1.67 (m, 2H), 2.69 (t,2H, J=7.6 Hz), 7.33 (d, 2H, J=8.3 Hz), 7.68 (dd, 1H, J=1.6, 5.2 Hz),7.91 (d, 1H, J=8.3 Hz), 8.20 (s, 1H), 8.72 (d, 1H, J=5.1 Hz).

2-(4-i-Propylphenyl)pyridine-4-carboxamide (8e): ¹H NMR (400 MHz,CD₃OD): δ 1.30 (d, 6H, J=6.9 Hz), 2.93-3.06 (m, 1H), 7.38 (d, 2H, J=8.2Hz), 7.67-7.69 (m, 1H), 7.93 (d, 2H, J=8.3 Hz) 8.21 (s, 1H), 8.73 (d,2H, J=5.1 Hz).

2-(4-Trifluoromethoxyphenyl)pyridine-4-carboxamide (8f): ¹H NMR (400MHz, CD₃OD): δ 7.30 (d, 2H, J=8.1 Hz), 7.67 (d, 1H, J=5.1 Hz), 8.02 (d,2H, J=8.1 Hz), 8.17 (s, 1H), 8.70 (d, 1H, J=5.1 Hz).

2-(4-Methoxyphenyl)pyridine-4-carboxamide (8g): ¹H NMR (400 MHz, CD₃OD):δ 3.82 (s, 3H), 6.98 (d, 2H, J=8.9 Hz), 7.59 (dd, 1H, J=1.6, 5.1 Hz),7.89 (d, 2H, J=8.8 Hz), 8.11 (s, 1H), 8.63 (d, 1H, J=5.1 Hz).

2-(4-Ethoxyphenyl)pyridine-4-carboxamide (8h): ¹H NMR (400 MHz, CD₃OD):δ 1.46 (t, 3H, J=7.0 Hz), 4.13 (q, 2H, J=7.0 Hz), 7.03 (d, 2H, J=8.9Hz), 7.63 (dd, 1H, J=1.6, 5.1 Hz), 7.94 (d, 2H, J=8.9 Hz), 8.16 (s, 1H),8.70 (d, 1H, J=5.2 Hz).

Example 3 2-[4-(4-Fluorophenoxy)phenyl]pyridine-3-carboxamide (10)

Compound 10 was prepared in a manner similar to the procedure describedfor compounds 8a-8h in Example 2 using compound 9 and4-(4-fluorophenoxy)phenyl boronic acid. ¹H NMR (400 MHz, CD₃OD). δ7.02-7.42 (m, 5H), 7.65 (d, 2H, J=8.8 Hz), 7.97-8.02 (m, 2H), 8.45 (d,1H, J=4.9 Hz), 8.68 (d, 1H, J=4.9 Hz).

2-[4-(4-Fluorophenoxy)phenyl]pyridine-4-carboxamide was preparedsimilarly using compound 7 and 4-(4-fluorophenoxy)phenyl boronic acid.¹H NMR (400 MHz, CDCl₃): δ 6.05 (bs, 1H), 6.31 (bs, 1H), 7.04-7.11 (m,6H), 7.51 (d, 1H, J=5.0 Hz), 8.03 (d, 2H, J=8.8 Hz), 8.10 (s, 1H), 8.81(d, 1H, J=5.0 Hz).

Example 4 5-(4-tert-Butylphenyl)pyridine-3-carboxamide (15a)5-(4-Phenoxyphenyl)pyridine-3-carboxamide (15b)5-(4-Ethoxyphenyl)pyridine-3-carboxamide (15c)5-(4-Methoxyphenyl)pyridine-3-carboxamide (15d)5-(4-n-Butylphenyl)pyridine-3-carboxamide (15e)5-(2-Naphthyl)pyridine-3-carboxamide (15f)5-(4-Thiomethylphenyl)pyridine-3-carboxamide (15g)5-(4-Trifluoromethoxyphenyl)pyridine-3-carboxamide (15h)5-(4-Trifluoromethylphenyl)pyridine-3-carboxamide (15i)

a) Compound 13: 20% piperidine in DMF was added topolystyrene-Rink-amide resin having 9-fluorenylmethoxycarbonyl (FMOC)protective group (PS-rink-NH-FMOC resin) (11) (4.45 g, 4.14 mmol) in asolid-phase reaction vessel, and the reaction was shaken for 1.5 hoursat ambient temperature. The resin was washed (DMF twice, dichloromethanetwice, DMF) and then treated again with 20% piperidine in DMF. It wasshaken for an additional hour, and the washing sequence was repeated.DMF was added to the resin, followed by N-hydroxybenzotriazole (HOBt)(3.4 g, 24.8 mmol), 5-bromonicotinic acid (5.0 g, 24.8 mmol), and asolution of 5-(3,4-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamide(DIC) (3.1 g, 24.8 mmol) in DMF. The mixture was shaken for 24 hours atambient temperature and then drained. The resin was washed (DMF twice,dichloromethane twice, DMF) and dried. Compound 13 was split intoindividual reaction vessels.

b) Compounds 14a-14i: 1,2-Dimethoxyethane (2.5 mL) was added to theindividual reaction vessels containing compound 13 (0.25 mmol), followedby the addition of the appropriate phenyl boronic acid (1.5 mmol). Tothis mixture was added water (1.0 mL), potassium carbonate (3.8 mmol),and Pd(PPh₃)₄ (0.043 mmol). The reactions were heated at 85° C. for 16hours. After returning to ambient temperature, the reactions weredrained, and the resin was washed (1:1 DME-water twice, water, 1:1DME-water twice, DME twice, water twice, THF twice, dichloromethanetwice) to yield compounds 14a-14i.

c) Compounds 15a-15i: Compounds 14a-14i were shaken in the presence of1:1 TFA-dichloromethane for 1.5 hours. The reactions were filtered, theresins were washed with dichloromethane, and the solvent was thenevaporated. Purification of compounds 15a-15i was carried out by firstfiltering over a bed of florisil followed by subjection to silica gelchromatography.

5-(4-tert-Butylphenyl)pyridine-3-carboxamide (15a): ¹H NMR (400 MHz,CD₃OD): δ 1.38 (s, 9H), 7.55 (d, 2H, J=8.6 Hz), 7.61 (d, 2H, J=8.5 Hz),8.50 (s, 1H), 8.91 (bs, 1H), 8.89 (bs, 1H).

5-(4-Phenoxyphenyl)pyridine-3-carboxamide (15b): ¹H NMR (400 MHz,CD₃OD): δ 7.06-7.42 (m, 7H), 7.67 (d, 2H, J=8.7 Hz), 8.49 (t, 1H, J=2.0Hz), 8.91 (bs, 1H), 8.98 (bs, 1H).

5-(4-Ethoxyphenyl)pyridine-3-carboxamide (15c): ¹H NMR (400 MHz, CD₃OD):δ 1.46 (t, 3H, J=7.0 Hz), 4.11 (q, 2H, J=7.0 Hz), 7.04 (d, 2H, J=8.6Hz), 7.62 (d, 2H, J=8.6 Hz), 8.56 (s, 1H), 8.92 (bs, 1H), 8.98 (bs, 1H).

5-(4-Methoxyphenyl)pyridine-3-carboxamide (15d): ¹H NMR (400 MHz,CD₃OD): δ 4.38 (s, 3H), 7.03 (d, 2H, J=8.8 Hz), 7.60 (d, 2H, J=8.8 Hz),8.80 (s, 1H), 8.95 (bs, 2H).

5-(4-n-Butylphenyl)pyridine-3-carboxamide (15e): ¹H NMR (400 MHz,CD₃OD): δ 1.03 (t, 3H, J=7.3 Hz), 1.44-1.49 (m, 2H), 1.70-1.76 (m, 2H),2.76 (t, 2H, J=7.6 Hz), 7.40 (d, 2H, J=8.8 Hz), 7.66 (d, 2H, J=8.8 Hz),8.59 (t, 1H, J=2.0 Hz), 8.98 (bs, 1H), 9.04 (bs, 1H).

5-(2-Naphthyl)pyridine-3-carboxamide (15f): ¹H NMR (400 MHz, CD₃OD): δ7.56-8.04 (m, 6H), 8.19 (s, 1H), 8.73 (s, 1H), 9.06 (bs, 1H), 9.12 (bs,1H).

5-(4-Thiomethylphenyl)pyridine-3-carboxamide (15g): ¹H NMR (400 MHz,CD₃OD): δ 2.49 (s, 3H), 7.33 (d, 2H, J=8.5 Hz), 7.55 (d, 2H, J=8.5 Hz),8.43 (s, 1H), 8.86 (bs, 1H), 8.92 (bs, 1H).

5-(4-Trifluoromethoxyphenyl)pyridine-3-carboxamide (15h): ¹H NMR (400MHz, CD₃OD): δ 7.34 (d, 2H, J=8.8 Hz), 7.69 (d, 2H, J=8.8 Hz), 8.46 (t,1H, J=2.1 Hz), 8.87 (bs, 1H), 8.99 (bs, 1H).

5-(4-Trifluoromethylphenyl)pyridine-3-carboxamide (15i): ¹H NMR (400MHz, CD₃OD): δ 7.78-7.83 (m, 4H), 8.54 (t, 1H, J=2.1 Hz), 8.95 (bs, 1H),9.07 (bs, 1H).

Example 5 2-(4-Trifluoromethoxyphenyl)pyridine-5-carboxamide (18a)2-(4-Trifluoromethylphenyl)pyridine-5-carboxamide (18b)2-(2-Naphthyl)pyridine-5-carboxamide (18c)2-(4-Phenoxyphenyl)pyridine-5-carboxamide (18d)2-(4-tert-Butylphenyl)pyridine-5-carboxamide (18e)2-(4-Ethoxyphenyl)pyridine-5-carboxamide (18f)2-(4-Thiomethylphenyl)pyridine-5-carboxamide (18g)2-(4-Methoxyphenyl)pyridine-5-carboxamide (18h)2-(4-n-Butylphenyl)pyridine-5-carboxamide (18i)2-(4-Phenylphenyl)pyridine-5-carboxamide (18j)

a) Compound 16: Compound 16 was prepared in a manner similar to theprocedure described for compound 13 in Example 4 using 6-chloronicotinicacid and compound 12.

b) Compounds 17a-17j: Compounds 17a-17j were prepared in a mannersimilar to the procedure described for compound 14 in Example 4 usingcompound 16 and the appropriate phenyl boronic acid.

c) Compounds 18a-18j: Compounds 18a-18j were prepared in a mannersimilar to the procedure described for compound 15 in Example 4.

2-(4-Trifluoromethoxyphenyl)pyridine-5-carboxamide (18a): ¹H NMR (400MHz, CD₃OD): δ 7.37 (d, 2H, J=8.0 Hz), 7.87 (d, 1H, J=8.3 Hz), 8.06 (d,2H, J=8.9 Hz), 8.32 (dd, 1H, J=2.3, 8.3 Hz), 9.10-9.11 (m, 1H).

2-(4-Trifluoromethylphenyl)pyridine-5-carboxamide (18b): ¹H NMR (400MHz, CD₃OD): δ 7.78 (d, 2H, J=8.0 Hz), 7.91 (d, 1H, J=8.2 Hz), 8.14 (d,2H, J=8.0 Hz), 8.35 (d, 1H, J=8.3 Hz), 9.14 (s, 1H).

2-(2-Naphthyl)pyridine-5-carboxamide (18c): ¹H NMR (400 MHz, CD₃OD): δ7.54-7.57 (m, 2H), 7.98-8.09 (m, 5H), 8.35 (dd, 1H, J=2.3, 8.3 Hz), 8.48(bs, 1H), 9.13 (d, 1H, J=2.2 Hz).

2-(4-Phenoxyphenyl)pyridine-5-carboxamide (18d): ¹H NMR (400 MHz,CD₃OD): δ 7.08-7.20 (m, 5H), 7.38-7.44 (m, 2H), 7.82 (d, 1H, J=8.3 Hz),7.97 (d, 2H, J=8.9 Hz), 8.29 (dd, 1H, J=2.3, 8.3 Hz), 9.07 (m, 1H).

2-(4-tert-Butylphenyl)pyridine-5-carboxamide (18e): ¹H NMR (400 MHz,CD₃OD): δ 1.32 (s, 9H), 7.52 (d, 2H, J=8.9 Hz), 7.81 (d, 1H, J=8.3 Hz),7.89 (d, 2H, J=8.9 Hz), 8.25 (dd, 1H, J=2.3, 8.3 Hz), 9.04 (d, 1H, J=2.3Hz).

2-(4-Ethoxyphenyl)pyridine-5-carboxamide (18f): ¹H NMR (400 MHz, CD₃OD):δ 1.46 (t, 3H, J=7.0 Hz), 4.13 (q, 2H, J=7.0 Hz), 7.03 (d, 2H, J=8.9Hz), 7.79 (d, 1H, J=8.4 Hz), 7.93 (d, 2H, J=8.9 Hz), 8.26 (dd, 1H,J=2.3, 8.4 Hz), 9.02 (d, 1H, J=2.2 Hz).

2-(4-Thiomethylphenyl)pyridine-5-carboxamide (18g): ¹H NMR (400 MHz,CD₃OD): δ 2.55 (s, 3H), 7.39 (d, 2H, J=8.9 Hz), 7.87 (d, 1H, J=8.3 Hz),7.93 (d, 2H, J=8.9 Hz), 8.31 (dd, 1H, J=2.3, 8.3 Hz), 9.09 (d, 1H, J=2.3Hz).

2-(4-Methoxyphenyl)pyridine-5-carboxamide (18h): ¹H NMR (400 MHz,CD₃OD): δ 3.90 (s, 3H), 7.05 (d, 2H, J=8.9 Hz), 7.81 (d, 1H, J=8.3 Hz),7.95 (d, 2H, J=8.9 Hz), 8.27 (dd, 1H, J=2.3, 8.3 Hz), 9.05 (d, 1H, J=2.3Hz).

2-(4-n-Butylphenyl)pyridine-5-carboxamide (18i): ¹H NMR (400 MHz,CD₃OD): δ 0.95 (t, 3H, J=7.3 Hz), 1.36-1.42 (m, 2H), 1.61-1.70 (m, 2H),2.69 (t, 2H, J=7.7 Hz), 7.33 (d, 2H, J=8.3 Hz), 7.83 (d, 1H, J=8.3 Hz),7.89 (d, 2H, J=8.3 Hz), 8.29 (dd, 1H, J=2.3, 8.3 Hz), 9.06 (d, 1H, J=2.3Hz).

2-(4-Phenylphenyl)pyridine-5-carboxamide (18j): ¹H NMR (400 MHz, CD₃OD):δ 7.37-7.69 (m, 5H), 7.70 (d, 2H, J=8.4 Hz), 7.95 (d, 1H, J=8.3 Hz),8.09 (d, 2H, J=8.4 Hz), 8.34 (dd, 1H, J=2.3, 8.3 Hz), 9.13 (d, 1H, J=2.1Hz).

Example 6 Activity of 2-[4-(4-fluorophenoxy)phenyl]pyridine 5-carboxylicacid 2-(N-piperidinyl)ethylamide as Sodium Channel Blocker

2-[4-(4-Fluorophenoxy)phenyl]pyridine 5-carboxylic acid2-(N-piperidinyl)ethylamide was tested in the electrophysiological assayas described above. The result of 2-[4-(4-fluorophenoxy)phenyl]pyridine5-carboxylic acid 2-(N-piperidinyl)ethylamide and other compounds arerepresented in Table 1.

TABLE 1 Evaluation of the Tested Compounds as Sodium Channel Blockersafter an Electrophysiological in vitro Assay RBIIA/β1 Compound nameK_(i)/μM 2-[4-(4-fluorophenoxy)phenyl]pyridine 5-carboxylic acid 2- 0.95(N-piperidinyl)ethylamide 5-[4-(4-fluorophenoxy)phenyl]pyridine3-carboxylic acid 2- 0.78 (N-piperidinyl)ethylamide2-[4-(4-fluorophenoxy)phenyl]pyridine-3-carboxamide 13.572-[4-(4-fluorophenoxy)phenyl]pyridine-4-carboxamide 6.912-(4-phenoxyphenyl)pyridine-5-carboxamide 14.622-(4-phenoxyphenyl)pyridine-4-carboxamide 22.285-(4-phenoxyphenyl)pyridine-3-carboxamide 5.435-(2-naphthyl)pyridine-3-carboxamide 35.122-(2-naphthyl)pyridine-5-carboxamide 28.062-(2-phenylphenyl)pyridine-4-carboxamide 24.852-(2-phenylphenyl)pyridine-5-carboxamide 40.685-(4-tert-butylphenyl)pyridine-3-carboxamide 18.552-(4-tert-butylphenyl)pyridine-4-carboxamide 53.122-(4-tert-butylphenyl)pyridine-5-carboxamide 32.322-(4-i-propylphenyl)pyridine-4-carboxamide 39.175-(4-thiomethylphenyl)pyridine-3-carboxamide 28.972-(4-thiomethylphenyl)pyridine-5-carboxamide 35.655-(4-trifluoromethoxyphenyl)pyridine-3-carboxamide 24.982-(4-trifluoromethoxyphenyl)pyridine-5-carboxamide 34.162-(4-trifluoromethoxyphenyl)pyridine-4-carboxamide 24.675-(4-trifluoromethylphenyl)pyridine-3-carboxamide 23.032-(4-trifluoromethylphenyl)pyridine-5-carboxamide 24.672-(4-n-butylphenyl)pyridine-4-carboxamide 32.922-(4-methoxyphenyl)pyridine-4-carboxamide 6.172-(4-ethoxyphenyl)pyridine-4-carboxamide 14.725-(4-ethoxyphenyl)pyridine-3-carboxamide 36.225-(4-methoxyphenyl)pyridine-3-carboxamide 54.415-(4-n-butylphenyl)pyridine-3-carboxamide 11.052-(4-ethoxyphenyl)pyridine-5-carboxamide 29.692-(4-methoxyphenyl)pyridine-5-carboxamide 44.562-(4-n-butylphenyl)pyridine-5-carboxamide 24.54

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents and publications cited herein are fully incorporated byreference herein in their entirety.

1. A compound having the Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Ar is Ar₃,wherein Ar₃ is

R₁ is C(O)R₁₀; R₂, R₃, and R₄ are independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, alkenyl, oralkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino,dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino,arylcarbonylamino, and aralkylcarbonylamino; provided that the pyridylring is other than 2,6-disubstituted with regard to Ar and R₁ or any ofR₂-R₄ that is other than hydrogen; R₅, R₆, R₇, and R₈ are independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,alkoxy, carboxy, carbonylamido and alkylthiol; and R₁₀ is selected fromthe group consisting of alkyl, alkenyl, alkynyl, OR₁₁, amino,alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl,dialkylaminoalkylamino, dialkylaminoalkenylamino,alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl,heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl,arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of whichare optionally substituted, wherein R₁₁ is selected from the groupconsisting of hydrogen, optionally substituted alkyl, and an alkalimetal.
 2. The compound of claim 1, wherein R₁₀ is selected from thegroup consisting of alkyl, alkenyl, OR₁₁, amino, alkylamino,dialkylamino, alkenylamino, dialkylaminoalkenyl, dialkylaminoalkylamino,and heterocycloalkylamino, all of which are optionally substituted. 3.The compound of claim 1, wherein R₂, R₃ and R₄ are independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,aminoalkyl, amino, hydroxyalkyl, alkoxy, aminocarbonyl,alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl,alkylcarbonylamino, arylcarbonylamino, and aralkylcarbonylamino.
 4. Thecompound of claim 3, wherein R₂ is selected from the group consisting ofhydrogen, alkyl, alkoxy, aminoalkyl and aminocarbonyl, and both R₃ andR₄ are hydrogen.
 5. The compound of claim 1, wherein R₅, R₆, R₇, and R₈are independently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro,amino, and cyano.
 6. The compound of claim 5, wherein R₅ and R₆ are bothhydrogen and R₇ and R₈ are independently selected from the groupconsisting of hydrogen, alkyl, halogen, haloalkyl, and nitro.
 7. Thecompound of claim 1, having the Formula V:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein: R₂-R₈ are defined in claim 1; and R₁₀ is amino or2-(N-piperidinyl)ethylamino; provided that the pyridyl ring is otherthan 2,6-disubstituted with regard to the biphenyl radical and —C(O)R₁₀or any of R₂-R₄ that is other than hydrogen.
 8. The compound of claim 7,wherein said compound is: 2-(4-phenylphenyl)pyridine-4-carboxamide;2-(4-phenylphenyl)pyridine-5-carboxamide; or a pharmaceuticallyacceptable salt thereof.
 9. A pharmaceutical composition, comprising thecompound of formula:

or a pharmaceutically acceptable salt thereof, wherein: Ar is Ar₃,wherein Ar₃ is

R₁ is C(O)R₁₀; R₂, R₃, and R₄ are independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, alkenyl, oralkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino,dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino,arylcarbonylamino, and aralkylcarbonylamino; provided that the pyridylring is other than 2,6-disubstituted with regard to Ar and R₁ or any ofR₂-R₄ that is other than hydrogen; R₅, R₆, R₇, and R₈ are independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,alkoxy, carboxy, carbonylamido and alkylthiol; and R₁₀ is selected fromthe group consisting of alkyl, alkenyl, alkynyl, OR₁₁, amino,alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl,dialkylaminoalkylamino, dialkylaminoalkenylamino,alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl,heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl,arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of whichare optionally substituted, wherein R₁₁ is selected from the groupconsisting of hydrogen, optionally substituted alkyl, and an alkalimetal; and a pharmaceutically acceptable carrier or diluent.
 10. Amethod for treating or ameliorating pain, comprising administering to amammal in need of such treatment or amelioration an effective amount ofa compound formula:

or a pharmaceutically acceptable salt thereof, wherein: Ar is Ar₃,wherein Ar₃ is

R₁ is C(O)R₁₀; R₂, R₃, and R₄ are independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, alkenyl, oralkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino,dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino,arylcarbonylamino, and aralkylcarbonylamino; provided that the pyridylring is other than 2,6-disubstituted with regard to Ar and R₁ or any ofR₂-R₄ that is other than hydrogen; R₅, R₆, R₇, and R₈ are independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,alkoxy, carboxy, carbonylamido and alkylthiol; and R₁₀ is selected fromthe group consisting of alkyl, alkenyl, alkynyl, OR₁₁, amino,alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl,dialkylaminoalkylamino, dialkylaminoalkenylamino,alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl,heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl,arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of whichcan be are optionally substituted, wherein R₁₁ is selected from thegroup consisting of hydrogen, optionally substituted alkyl, and analkali metal.
 11. The method of claim 10, wherein said pain is one ofneuropathic pain, surgical pain or chronic pain.
 12. A compound havingthe Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Ar is Ar₃,wherein Ar₃ is

R₁ is C(O)R₁₀; R₂, R₃, and R₄ are independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, alkenyl, oralkynyl, halogen, hydroxy, cycloalkyl, cyano, amino, alkylamino,dialkylamino, alkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino,arylcarbonylamino, and aralkylcarbonylamino; provided that the pyridylring is other than 2,6-disubstituted with regard to Ar and R₁ or any ofR₂-R₄ that is other than hydrogen; R₅, R₆, R₇, and R₈ are independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,alkoxy, carboxy, carbonylamido and alkylthiol; and R₁₀ is selected fromthe group consisting of alkyl, alkenyl, alkynyl, OR₁₁, amino,alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl,dialkylaminoalkylamino, dialkylaminoalkenylamino,alkylaminoalkenyl-amino, hydroxyaminoalkenylamino, cycloalkyl,heterocycloalkyl, cycloalkylalkylamino, heterocycloalkylamino, aryl,arylalkyl, arylalkenyl, arylalkynyl, and arylalkylamino, all of whichare optionally substituted, wherein R₁₁ is selected from the groupconsisting of hydrogen, optionally substituted alkyl, and an alkalimetal; wherein said compound is ³H or ¹⁴C radiolabeled.
 13. A method ofscreening for a candidate compound for treating or ameliorating painthat binds to a receptor using a radiolabeled compound of claim 12,comprising: introducing a fixed concentration of the radiolabeledcompound to the receptor to form a mixture; titrating the mixture with acandidate compound; and determining the binding of the candidatecompound.